Rheumatoid Arthritis (RA) (exam 6)

rheumatoid arthritis (RA)

A chronic, progressive autoimmune disease causing inflammation in the joints and other body systems. Which results in painful deformity and immobility. Most commonly seen in the fingers, wrists, feet, and ankles. Affects more than just joints. Can affect skin, eyes, lungs, heart and blood vessels

Abatacept (Orencia) binds CD80/CD86 receptors on antigen-presenting cells and Inhibits interaction between APC and T-cells, prevents T-cell activation What is this medication indicated for?

moderate to severe RA as monotherapy or combo typically in patients who fail to achieve an adequate response from other DMARDs AEs: headache, nasopharyngitis, dizziness, cough, back pain, hypertension, dyspepsia, urinary tract infection, rash, and extremity pain -Infusion reactions -Increase risk of infection -No live vaccines during and for 3 months after the completion of therapy

Prognostic (risk) factors of RA:

•High tender and swollen joint counts •Radiographic erosions •Elevated RF / ESR / CRP •Elevated anti-CCP antibodies •Age •Female •Genetics •Tobacco use •Worsening physical function

Sulfasalazine is indicated for all disease durations and severities. What are the dosing considerations with this medication?

0.5 - 1 gm PO daily x 1 week [enteric coated] Inc. daily dose by 500mg q week until 2 gm TDD (3 gm max) Can titrate more slowly or divide dose to minimize AE

Epidemiology of rheumatoid arthritis:

-1% prevalence of the population -Prevalence increases with age up to 70s -3 times more common in women (6:1 in 15-45 age bracket) -Genetic predisposition -Environmental exposure

Extraarticular Involvement of Rheumatoid arthritis includes blurred vision, vasculitis that can progress to ulcers, neurological symptoms and nodules (20% of pts). What are characteristics of nodules?

-Bumps on joints -Most common on the extensor surfaces of the elbows, forearms, and hands -Asymptomatic Others: Cardiac, Pulmonary, Lymphadenopathy (swollen), Splenomegaly, Felty Syndrome (RA, splenomegaly and neutropenia, resulting in susceptibility to bacterial infections)

Non-pharm that really works: Lets start here by asking, "why is the immune system so upset?" When in doubt, look at the gut -- 5Rs

-Chances are dysbiosis/lifestyle-induced IP/leaky gut -SAD -Remove, Replace, Re-inoculate, Repair, Rebalance -Elimination diet -Probiotic

BBW indicated with Rituximab (Rituxan) includes?

-Deaths have occurred, typically first infusion -Mucocutaneous reactions: fatal reactions have occurred -Hepatitis B virus reactivation -Progressive multifocal leukoencephalopathy Precaution/warning -Adverse cardiac effects (v. fib, MI) -Lymphopenia, leukopenia, neutropenia, thrombocytopenia, and anemia

The main AE of Methotrexate are THROMBOCYTOPENIA & FOLATE DEPLETION others include what?

-GI: N/V/D, elevated liver enzymes -Leukopenia -Pulmonary Fibrosis and pneumonitis - rare

Treating to target helps to keep providers regularly following up with patients and reminds them to adjust therapy more frequently when clinically warranted. What are good approaches?

-Identify a target of therapy (remission, reduction in activity score, etc.) and a method for monitoring -Monitoring at predetermined intervals -A plan to change therapy if the target is not achieved at monitoring point -Collaboration and shared decision-making with the patient

Biologic DMARDs are historically reserved for Tx failure (mod. to severe), expensive and is involved with less toxicities with less monitoring which results in what?

-Increase risk of infection -Must test for TB prior to initiation of therapy -If develop infection should discontinue until infection is resolved -No live vaccines should while taking biologics

Corticosteroids are great for flares and adjunct (bridge therapy/combo) but not for monotherapy despite anti-inflammatory and immunosuppressive effects. What purpose do they serve?

-Low-dose glucocorticoid ≤10 mg/day of prednisone (or equivalent) -High-dose glucocorticoid >10 mg/day of prednisone (or equivalent) and up to 60 mg/day with a rapid taper -Short-term glucocorticoid <3 month treatment

Anakinra (Kineret) Interleukin - 1 Receptor Antagonist, a Natural anti-inflammatory that is indicated for what?

-Moderate to severe active RA in patients 18 years and older who have failed 1 or more DMARDs -Neonatal-onset multisystem inflammatory disease

Tofacitinib (Xeljanz) Humanized monoclonal antibody that prevents IL-6 from interacting with the IL-6 receptor. This medication can be used monotherapy or in combination with methotrexate or other nonbiologic DMARDs. What is this medication indicated for?

-Moderate to severe rheumatoid arthritis, have failed other therapies, typically MTX or another biologic -Psoriatic arthritis: if inadequate response/intolerance to methotrexate or other DMARDs -Ulcerative colitis: moderate to severe

AE of Leflunomide (Arava) are dose related and includes:

-N/V/D -Alopecia -Bone marrow suppression -CBC monthly x 6 months, then q 6-8 weeks -Contraindicated in liver disease -LFTs >2x ULN = Stop -Monitor LFTs monthly x 3 months then quarterly -Pregnancy Category X Monitor TB at baseline and preg. test prior to initiating

Pharm therapies for RA include what?

-NSAIDs -Corticosteroids -Disease-modifying antirheumatic drug=DMARD TNF-α inhibitors Non-TNF biologics Tofacitinib

Tofacitinib (Xeljanz) is dosed in both extended and immediate release. Match the following terms to their correct dosages. Not recommended to combine with biologics or potent immunosuppressants (azathioprine, cyclosporine) 1. Immediate release: 2. Extended release:

1. 5 mg PO twice daily 2. 11 mg PO once daily

Treatment strategies of RA:

1. DMARD Monotherapy 2. Combination therapy -Dual Methotrexate plus hydroxychloroquine Methotrexate plus leflunomide Methotrexate plus sulfasalazine -Triple DMARDs Sulfasalazine, hydroxychloroquine, and methotrexate

Pathophysiology of rheumatoid arthritis involves inflammation of the synovial tissue lining the joint. What happens during this process?

1. Immune system attacks the synovial and other connective tissues 2. Chronic inflammation leads to proliferation of the tissue, results in a pannus (abnormal layer tissue) Eventually the pannus invades the cartilage then the bone, ultimately causing destruction of the joint

Match the following characteristics below to their appropriate terms regarding Rheumatoid Arthritis: 1. ≥ 6 weeks of joint pain and/or stiffness (deformity not until later in disease progression) Fatigue, weakness, low-grade fever, loss of appetite 2. Tenderness, warmth, and swelling in affected joints (hands and feet); Symmetrical joint; nodules are possible

1. Symptoms 2. Signs

Anakinra (Kineret) is considered to be used when you have failed everything else. What is its dosing?

100 mg SQ daily at same time each day -Can't combine with TNF inhibitors -Infections, malignancy, neutropenia, inject rx

Dosing considerations of Rituximab (Rituxan) include what?

1000 mg IV infusion on days 1 and 15 with MTX -Administer subsequent courses every 24 weeks of based on clinical symptoms (No sooner than q 16 weeks) Infusion rx: premedicate with acetaminophen and an antihistamine prior to infusion

Upadacitinib (Rinvoq) can be used monotherapy or in combination with methotrexate or other nonbiologic DMARDs. How is this medication dosed?

15 mg PO once daily Do not use with other JAK, biologic, or potent immunosuppressant Do not start if absolute lymphocyte count <500/mm3, ANC <1,000/mm3, or hemoglobin <8 g/dL

Sarilumab (Kevzara) Monotherapy or combo with nonbiologic DMARDs; Do not initiate if ANC is <2,000/mm3, platelets are <150,000/mm3 or if ALT or AST are >1.5 times ULN. How is this medication dosed?

200 mg SQ q 2 weeks If side effects occur, reduce to 150 mg Monitor: neutrophils/platelets/lipid panel 4-8wks

Baricitinib (Olumiant) can be used monotherapy or in combination with methotrexate or other nonbiologic DMARDs. How is this medication dosed?

2mg PO daily BBW: -Serious infections -Malignancies -Thrombosis

Adalimumab (Humira) is a Anti-TNFα monoclonal antibody (IgG1) that binds to TNF-alpha, interfering with binding to TNFα receptors that is indicated for adults with moderate to severe active RA AND Psoriasis & Psoriatic Arthritis. Juvenile idiopathic arthritis, Crohn's disease, Ulcerative colitis, & Ankylosing spondylitis. What is the dosing of this medication?

40 mg SQ every other week can continue methotrexate, other nonbiologic DMARDS, corticosteroids, NSAIDs, and/or analgesics patients not taking concomitant methotrexate may increase dose to 40 mg every week

Certolizumab pegol (Cimzia) is a pegylated humanized antibody fragment to TNF-alpha and indicated for moderate to severe active RA, Plaque psoriasis, Psoriatic Arthritis, Crohn's, & Ankylosing spondylitis. What is the dose of this medication?

400mg SQ at Week 0, 2, 4, then 200mg every other week -Alternative maintenance dose: 400 mg SQ every 4 weeks -Alone or with MTX AEs similar to TNF Profile: Infections 38%; URI 6-20%

Golimumab (Simponi) is a Human monoclonal antibody to TNF-alpha that is indicated for moderate to severe active RA with methotrexate, Psoriatic Arthritis, UC, Ankylosing spondylitis. What is the dose of this medication?

50 mg SQ once monthly with methotrexate IV: 2 mg/kg at weeks 0, 4, and then every 8 weeks thereafter with methotrexate AEs similar to TNF profile

Etanercept (Enbrel) binds tumor necrosis factor (TNF) and blocks its interaction with cell surface receptors and is a recombinant DNA-derived protein composed of tumor necrosis factor receptor (TNFR) linked to the Fc portion of human IgG1. what is the dose of this medication?

50 mg SQ once weekly (off-label 25 MG BIW) -Typically self injection -may continue methotrexate, glucocorticoids, salicylates, NSAIDs, or analgesics during etanercept therapy

What medications also treat Plaque Psoriasis & Psoriatic Arthritis. Juvenile idiopathic arthritis, Crohn's disease, Ulcerative colitis, & Ankylosing spondylitis?

Adalimumab (Humira) Infliximab (Remicade) Golimumab (Simponi) Certolizumab pegol (Cimzia)

NSAIDs for the use of RA is a great option for adjunct therapy however it is not used for monotherapy despite anti-inflammatory effects because it does not alter the progression of diseases. What purpose does do they serve?

Analgesia and anti-inflammatory -Inhibit PG synthesis not enough -Reduces pain and stiffness

Non-biologic DMARDs for RA include:

Methotrexate (Rheumatrex, MTX) -- PO, SQ, IM Leflunomide (Arava) - ProDrug Hydroxychloroquine (Plaquenil) Sulfasalazine -- ProDrug

What is a major warning of TNF inhibitors?

CHF: increased risk of worsening and new-onset CHF Contraindicated in moderate-to-severe CHF (NYHA class III/IV)

What are key inflammatory mediators?

Cytokines: TNF, IL-1, IL-6 Soluble Mediators: Prostaglandins, Leukotrienes, Matrix metalloproteinases

Definitions per the Guidelines

DMARD monotherapy -Most often defined as the use of MTX monotherapy, but may also be SSZ, HCQ, or LEF Double DMARD therapy -MTX+SSZ, MTX+HCQ, SSZ+HCQ, or combinations with LEF Triple DMARD therapy -MTX+SSZ+HCQ DMARD combination therapy -Double or triple traditional/conventional DMARD therapy

This DMARD is known as the initial of choice with anti-inflammatory action, fast onset, with a pregnancy cat. X and no for lactation.

Methotrexate (Rheumatrex, MTX) -- least expensive 2-3 wks for initial effect, improv. up to 12 CI: CrCl < 40ml/min, liver dx, immunodef., pleural or peritoneal effusions, leukopenia, thrombocytopenia, preexisting blood disorders

The following characteristics below describes what? -Synovitis of at least one joint and no other explanation -Positive laboratory tests including RF, ACPA, CRP, and ESR -Duration of symptoms more than or equal to 6 weeks -Criteria: ≥ 6/10

Diagnosis of RA

RA lasts 30min-All day and mainly affects the what although it progresses to more joints as inflammation continues?

Hands, feet, Wrists Persistent inflammation and proper exercise is diminished → Joint deformity

The following characteristics below describe which medication? -Anti-malarial -MoA unknown: Reduces antigen-antibody response at site of inflammation perhaps by affecting cellular migration and activation -Onset of action up to 6 weeks -Treatment failure only if no response > 6 months -Place in therapy d/t NO myelosuppressive, NO hepatic and renal toxicities

Hydroxychloroquine (Plaquenil)

Infliximab (Remicade) is a chimeric monoclonal antibody (mouse and human) indicated for adults with moderate to severe active rheumatoid arthritis with methotrexate. What is the dose of this medication?

IV 3 mg/kg at 0, 2, and 6 weeks, followed by 3 mg/kg every 8 weeks thereafter -Response seen in 4 weeks -Infuse over 2 hours -Begin infusion within 3 hours of reconstitution May lose efficacy due to antibody development (murine component) -- 14-40% of patients

What are dosing considerations regarding Abatacept (Orencia)?

IV infusion over 30 minutes, Weight based Dose IV at weeks 0, 2, and 4, then q 4 weeks thereafter >100 kg - 1000 mg 60 - 100 kg - 750 mg <60 kg - 500 mg

Tocilizumab (Actemra) You must monitor neutrophils / platelets and don't initiate among pts with ANC <2000, PLT <100,000 or LFT >1.5x ULN. How can this medication be initiated?

IV: 4 mg/kg every 4 weeks; may inc. to 8 mg/kg once every 4 weeks based on clinical response (max: 800 mg) SubQ: <100 kg: 162mg once every other wk; inc. to 162 mg once every week based on clinical response ≥100 kg: 162mg once every week

Recommendations on use a treat-to-target strategy over a non-targeted approach:

In patients who have never taken a DMARD with low, moderate, or high disease activity, use DMARD monotherapy over double and triple therapy -MTX If disease activity remains moderate to high with DMARD monotherapy, add a DMARD (double DMARD), or a TNFi or a non-TNF biologic

Which medications must be given with methotrexate?

Infliximab (Remicade) Golimumab (Simponi)

___________________ is a ProDrug, inhibits pyrimidine, has a long t1/2, and has a loading dose of 100mg QD x3 then maintenance dose of 20mg QD.

Leflunomide (Arava) -Any disease duration / severity -Can decrease if SE -w/o loading dose, steady state takes MONTHS to achieve

The following dosing characteristics below describes which medication? -Start 7.5 mg once weekly -Typical 10 to 15 mg once weekly -Increase by 5 mg every 2 to 4 weeks to a maximum of 20mg (30 mg) once weekly -PO doses >15 mg, may want to switch routes d/t BA -Alternate dosing: 2.5 mg PO q 12 hours for 3 doses every week

Methotrexate (Rheumatrex, MTX) -- PO, SQ, IM -Add folic acid 1mg PO daily -Consider IM/SQ if GI side effects

What are the supportive therapies used for RA?

NSAIDs Corticosteroids

Infliximab (Remicade) ADRs related to infusion involve Pruritus / urticaria, Chest pain, hypotension, SOB. How would you minimize infusion reactions?

Pre-medicate -APAP and diphenhydramine 90 minutes prior to infusion -Corticosteroids Slow rate of infusion OR Give with MTX or other immunosuppressants Cases of hepatotoxicity and flu-like symptoms occur: fever, chills, fatigue, diarrhea, pharyngitis, HA, CNS complications

Adverse effects of Etanercept (Enbrel):

Pruritic injection site reactions (up to 43%) -lasts 3-5 days x 1st month, then better Other ADRs are similar to the TNF profile -Headache (19%) -Infection (up to 81%) -URTI & LRTI Common: 65% and 54%, respectively Monitor baseline & yearly: PPD, CBC, LFTs

The following characteristics below describe which medication? -Monoclonal chimeric antibody to CD20 protein found on the cell surface of B lymphocytes -Results in depletion peripheral B cells: B cells takes months to recover -Intermittent therapy possible -Useful in patients who have failed MTX or TNFi's -Combine with MTX for best results -NO LIVE VACCINES

Rituximab (Rituxan)

The following characteristics below describe which medication? -Prodrug -Cleaved by gut bacteria in the colon to sulfapyradine and 5-ASA (IBD)--What happens in SIBO or gut dysbiosis?? -In this case the sulfapyradine is responsible for effect -Response seen in < 2 months -Binds Fe-limits absorption

Sulfasalazine -AE: yellow-orange skin and urine; CI in hypersensitivity

__________ induces inflammatory cytokines (interleukins), enhances leukocyte migration, activates neutrophils and eosinophils, and induces acute phase reactants and tissue degrading enzymes

TNFα

Hydroxychloroquine (Plaquenil) is indicated for all disease durations and severities. How should this medication be taken?

Take with food Start: 200-300 PO mg BID After clinical response or 1-2 months, decrease to 200 mg daily or 200 mg BID

The following characteristics below describe which medications? -IL-6 blocker -Moderate to severe active RA -Failed 1 or more TNF inhibitor (DMARDs) -Can increase LFTs, LDL, HTN, GI perforations

Tocilizumab (Actemra) Sarilumab (Kevzara)

Janus Kinase Inhibitors

Tofacitinib (Xeljanz) Baricitinib (Olumiant) Upadacitinib (Rinvoq)

T/F: Antibodies directed against the Fc portion of Immunoglobulin G (IgG) are also present in other autoimmune disorders, chronic and acute infection, and cancer.

True Normal range: <24 IU/mL Low positive: 24-72 IU/mL (1-3X ULN) High positive: >72 IU/mL (>3X ULN)

Which of the following medications have BBW as such below? -Serious infections -Malignancies -Thrombosis

Upadacitinib (Rinvoq) Baricitinib (Olumiant)

Anticitrullinated protein antibody (ACPA) may be present before symptoms of RA however is another antibody that's produced in most RA patients, present during inflammation, as well as what?

Used as a diagnostic aid, not definitive Positive antibodies = poorer prognosis Serology -Normal value - < 20 EU/mL -20-39 EU/mL - Weakly positive -40-59 EU/mL - Moderately positive -> 60 EU/mL - Strongly positive

American College of Rheumatology White Paper A "_____________" is a biologic product that is extremely similar to an approved reference biologic and doesn't not have clinically significant differences in efficacy, adverse effects, or immunogenicity compared to the reference product

biosimilar -An approved biosimilar should produce clinical outcomes comparable to those achieved with its reference product -Providers are encouraged to integrate biosimilars into their practices with the goal of quality health care at lower cost to patients

Many RA patients form antibodies to self called rheumatoid factors but this does not correlate with level of disease activity however it is used to do what?

help make a diagnosis Seropositive patients tend to have a more aggressive disease

Dysregulation of TNF-α production is associated with _____________. E.g. RA, IBD, ankylosing spondylitis, PsA, and psoriasis

inflammation •Etanercept (Enbrel) •Infliximab (Remicade) •Adalimumab (Humira) •Certolizumab pegol (Cimizia) •Golimumab (Simponi)

Treatment goals of RA

•Achieve remission or lower disease activity (Treat to Target) •Reduce progression of disease •Reduce risk of joint damage & maintain function of joints •QOL-pain

What DMARDs are limited by toxicities and LT benefits?

•Gold salts •Azathioprine •D-penicillamine •Cyclosporine •Minocycline •Cyclophosphamide